BR112016028616A8 - compostos químicos, seus usos, e composição farmacêutica - Google Patents

compostos químicos, seus usos, e composição farmacêutica

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Publication number
BR112016028616A8
BR112016028616A8 BR112016028616A BR112016028616A BR112016028616A8 BR 112016028616 A8 BR112016028616 A8 BR 112016028616A8 BR 112016028616 A BR112016028616 A BR 112016028616A BR 112016028616 A BR112016028616 A BR 112016028616A BR 112016028616 A8 BR112016028616 A8 BR 112016028616A8
Authority
BR
Brazil
Prior art keywords
compounds
hcv
pharmaceutical composition
chemical compounds
ns5a
Prior art date
Application number
BR112016028616A
Other languages
English (en)
Other versions
BR112016028616B1 (pt
BR112016028616A2 (pt
Inventor
James Zhan Zheng-Yun
Original Assignee
Ab Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ab Pharma Ltd filed Critical Ab Pharma Ltd
Publication of BR112016028616A2 publication Critical patent/BR112016028616A2/pt
Publication of BR112016028616A8 publication Critical patent/BR112016028616A8/pt
Publication of BR112016028616B1 publication Critical patent/BR112016028616B1/pt

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41781,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50Pyridazines; Hydrogenated pyridazines
    • A61K31/502Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/056Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems
    • C07D491/113Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D493/00Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

compostos para inibir vírus da hepatite c, composições farmacêuticas e usos dos mesmos. o proporciona uma classe de compostos que inibem o vírus da hepatite c (vhc), e estereoisómeros, tautómeros, isómeros isotópicos, hidratos, pró-fármacos esterificado ou amidado, os seus sais farmaceuticamente aceitáveis, composições farmacêuticas e utilizações dos mesmos, e misturas de um ou mais componentes da composição no fabrico de um medicamento para inibir a aplicação de hcv, os compostos podem ser eficazes para inibir a hcv-ns5a, os pode ser usado para a preparação de a prevenção e/ou tratamento de hcv-ns5a de doenças infecciosas.
BR112016028616-2A 2014-06-06 2014-12-03 Compostos químicos, seus usos, e composição farmacêutica BR112016028616B1 (pt)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/CN2014/079386 WO2015184644A1 (zh) 2014-06-06 2014-06-06 抑制丙肝病毒的化合物、药物组合物及其应用
CNPCT/CN2014/079386 2014-06-06
PCT/CN2014/092902 WO2015184753A1 (zh) 2014-06-06 2014-12-03 抑制丙肝病毒的化合物、药物组合物及其应用

Publications (3)

Publication Number Publication Date
BR112016028616A2 BR112016028616A2 (pt) 2017-08-22
BR112016028616A8 true BR112016028616A8 (pt) 2021-07-20
BR112016028616B1 BR112016028616B1 (pt) 2021-10-05

Family

ID=54765978

Family Applications (1)

Application Number Title Priority Date Filing Date
BR112016028616-2A BR112016028616B1 (pt) 2014-06-06 2014-12-03 Compostos químicos, seus usos, e composição farmacêutica

Country Status (18)

Country Link
EP (1) EP3153515B1 (pt)
JP (1) JP6523440B2 (pt)
KR (1) KR102025415B1 (pt)
AU (1) AU2014396578C1 (pt)
BR (1) BR112016028616B1 (pt)
CA (1) CA2951317C (pt)
DK (1) DK3153515T3 (pt)
ES (1) ES2829920T3 (pt)
HU (1) HUE051356T2 (pt)
IL (1) IL249403B (pt)
MX (1) MX2016016119A (pt)
MY (1) MY178515A (pt)
PE (1) PE20170266A1 (pt)
PL (1) PL3153515T3 (pt)
PT (1) PT3153515T (pt)
RU (1) RU2671194C2 (pt)
SG (1) SG11201610453SA (pt)
WO (2) WO2015184644A1 (pt)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109232612A (zh) * 2017-07-11 2019-01-18 周龙兴 抑制丙肝病毒的化合物、药物组合物及其用途
CN111118073B (zh) * 2019-12-27 2022-02-15 宜昌东阳光生化制药有限公司 酶法合成依米他韦中间体的方法

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558059B (zh) * 2006-08-11 2014-12-03 百时美施贵宝公司 丙型肝炎病毒抑制剂
US8329159B2 (en) * 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7704992B2 (en) * 2008-02-13 2010-04-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8147818B2 (en) * 2008-02-13 2012-04-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
BRPI0822323A2 (pt) * 2008-02-13 2015-06-16 Bristol Myers Squibb Co Imidazolil bifenil imidazóis como inibidores do vírus da hepatite c
US8729077B2 (en) * 2008-11-28 2014-05-20 Glaxosmithkline Llc Anti-viral compounds, compositions, and methods of use
WO2010096462A1 (en) * 2009-02-17 2010-08-26 Enanta Pharmaceuticals, Inc Linked diimidazole derivatives
EA020898B1 (ru) * 2009-03-27 2015-02-27 Мерк Шарп Энд Домэ Корп. Ингибиторы репликации вируса гепатита c
NZ706236A (en) * 2009-05-13 2016-07-29 Gilead Pharmasset Llc Antiviral compounds
MX2012006877A (es) * 2009-12-18 2012-08-31 Idenix Pharmaceuticals Inc Inhibidores de virus de hepatitis c de arileno o heteroarileno 5, 5 - fusionado.
US20130072523A1 (en) * 2009-12-24 2013-03-21 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
CA2800509A1 (en) * 2010-05-24 2011-12-01 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
US8778938B2 (en) * 2010-06-04 2014-07-15 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011156543A2 (en) * 2010-06-09 2011-12-15 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a protein
US20120195857A1 (en) * 2010-08-12 2012-08-02 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
SG10201509456SA (en) * 2010-11-17 2015-12-30 Gilead Pharmasset Llc Antiviral compounds
BR112014000563A2 (pt) * 2011-07-09 2019-12-10 Sunshine Lake Pharma Co., Ltd composto, composição farmacêutica, e, uso do composto
TW201439084A (zh) * 2012-11-29 2014-10-16 Sunshine Lake Pharma Co Ltd 作爲丙型肝炎抑制劑的螺環化合物、藥物組合物及它們在藥物中的應用
CN111116563B (zh) * 2013-06-06 2023-07-04 上海爱博医药科技有限公司 抑制丙肝病毒的化合物、药物组合物及其应用
SG11201608587QA (en) * 2014-04-15 2016-11-29 Cocrystal Pharma Inc Potent and selective inhibitors of hepatitis c virus

Also Published As

Publication number Publication date
EP3153515A1 (en) 2017-04-12
EP3153515B1 (en) 2020-08-12
PE20170266A1 (es) 2017-04-14
KR20170005382A (ko) 2017-01-12
RU2016151193A (ru) 2018-07-17
JP6523440B2 (ja) 2019-05-29
AU2014396578C1 (en) 2019-04-11
WO2015184753A1 (zh) 2015-12-10
PL3153515T3 (pl) 2021-03-08
AU2014396578A1 (en) 2017-01-19
JP2017521484A (ja) 2017-08-03
HUE051356T2 (hu) 2021-03-01
IL249403B (en) 2021-01-31
KR102025415B1 (ko) 2019-09-25
MX2016016119A (es) 2017-03-28
SG11201610453SA (en) 2017-02-27
IL249403A0 (en) 2017-02-28
BR112016028616B1 (pt) 2021-10-05
EP3153515A4 (en) 2018-07-25
BR112016028616A2 (pt) 2017-08-22
RU2671194C2 (ru) 2018-10-30
DK3153515T3 (da) 2020-11-09
CA2951317C (en) 2019-10-01
MY178515A (en) 2020-10-15
AU2014396578B2 (en) 2018-11-22
WO2015184644A1 (zh) 2015-12-10
ES2829920T3 (es) 2021-06-02
CA2951317A1 (en) 2015-12-10
RU2016151193A3 (pt) 2018-07-17
PT3153515T (pt) 2020-11-11

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